The bony defects surgically created from tumor excision or skeletal trauma claim more than 0.5 million bone-grafting procedures in the United States annually. Autograft (bone taken from one part of the body and transferred to another part of the same individual) and allograft (bone taken from foreign body and transferred to a different individual) transplanted tissues and synthetic biomaterials usually are implanted for enhancing bone regeneration. Although tissue transplants usually have better efficacy, restrictions of inadequate sources of autograft as well as disease transfer risks limit the relevant applications. The biodegradable bone grafts in bone tissue engineering serve as temporary void fillers that can gradually be degraded and replaced by the regenerated bone tissues. Synthetic bone graft materials are preferred due to their biocompatibility, osteoconduction, and little risk of disease transmission. Typical ceramic bone graft materials such as hydroxyapatite (HA, Ca10(PO4)6(OH)2), β-tricalcium phosphate (β-TCP, β-Ca3(PO4)2) and calcium sulfate (CS, CaSO4), can be presented in different product forms such as powder, granule, pellet, putty, or block to apply to various bone damage conditions. However, these materials are mostly available in particulate or solid bulk without desired porous structure for cells and blood vessels ingrowth. Thus, the use of such materials in orthopedic and dental applications has been limited.
The porous structures of the scaffolds are especially important in tissue engineering for cells attachment and cells ingrowth to support osteocyte proliferation and differentiation. The pore size of the scaffold structure is crucial for osteoconduction. If the pore size is less than 100 μm, the bone tissue may accumulate on the graft surface only. After the implantation, the bone graft should be gradually degraded and replaced by the recipient's own bones. Pores can be categorized as either open-cell or closed-cell. The connectivity of three-dimensional pores is open-cell type which is designed to mimic the in vivo environment for enhancing the blood vessel ingrowth into the defect area.
At present, many fabrication methods for bone grafts have been developed and summarized in Table 1. Most of the commercial bone grafts are granular type. There is certain type of 3D open-cell bone grafts available. They are either fabricated by series tedious procedures or derived from naturally occurring materials like animal bones or marine (sea coral) life. Naturally occurring materials have the fixed composition such as hydroxyapatite or calcium carbonate; the degradation time of hydroxyapatite is too long, while the degradation of calcium carbonate is too short. Thus, they cannot provide suitable degradation time to meet all the requirements for various clinical applications.
TABLE 1Product name(producer, factory)Composition (content)Comments (phase)Healos (Depuy Spine)SpongeParticulate or block brittle.ProOsteon (Interpore Int.,Radiopaore size 190-230 μm)USA) Previous name: Replam500: Porites Gonipora (largeHydroxyapatite-Porites orpores) R: Resorbcity impedesRHAPassessment of healing. Slowresorption R-formCollagraft (Zimmer Inc, USA)HA coated 70% Type I bovineGranules and strips requirecollagenaugmentation with aspiratedmarrowMBCP (Biomatlante)Replaniform corallineGranules, rectangular sticks,macroporous HA 200: Poritescylinders or wedges(pableTriosite (Zimmer Europe Ltd,60% HA, 40% TCPAlso called MBCPUK)(macroporous biphasiccalcium phosphate) or BCPBCP (Bioland)60% HA, 40% TCPOstilit (Stryker Howmedica20% HA, 80% TCP, withoutGranules and blocks forOsteonics, UK)macroporousnonstructural graftsBoneSave (Stryker20% HA, 80% TCP,Granules, stronger than Ostilit,Howmedica Osteonics, UK)pore size: 400-600 μmfor use as a void filler and ingraftingCerasorb ORTHO (curasan)Pure phase β-TCP,Granular size being 500-1,000micropores: <80 μmμm or 1,000-2,000 μmVitoss ™ Scaffold (curasan)β-TCP, micropores: <1-1000Morsel (1-4 mm sizes) andμmblocks (9 × 23 mm cylinder)Conduit ™ TCP Granules>99% (β-TCP) Ca3(PO4)2,Irregular shaped granules(DePuy Spine)pore: 1-600 μmhaving an average diameterbetween 1.5 and 3 mmCellplex ™ TCP syntheticPorous calcium phosphatecancellous bone (Wright)made from TCP, pore size:100-400 μmCeros 82β-TCP, porosity varies toLower compressive strengthadjust resorption between 6than Ceros 80and 12 monthsSynthes (USA) chronOS ™β-TCP pore size: 100-500 μmGranules, blocks, wedge and(Synthes)cylindersCalciresorb (Ceraver Osteal, Porous TCPPeriodontal applicationsFrance)Synthograf (Milter, USA)Small size and dense TCPPeriodontal applicationsAugmen (Milter, USA)Large size and dense TCPPeriodontal applicationsSkelite ™ (MilleniumMultiphase, porous calciumGranules and blocksBiologix)phosphateNorian Skeletal Repair SystemSelf-setting calcium phosphateInjectable cement,(SRS)cementaugmentation of fracture
The prior art of different methods to form artificial porous bone grafts can be divided into several categories:
1. Dissolving and Washing
WO 20061099332A2 discloses a method of producing porous artificial composite. The method comprises using salt grains as a porogen, mixing them with calcium phosphate materials, shaping the mixture by pressing, sintering, and then dissolving the salts to form pores structure. However, this process has the disadvantage that the steps are complicated. In addition, most pores formed in the process are closed and lack of connectivity. Also, the dissolving step after sintering cannot effectively wash out the salt grains that are left inside.
2. Gasification
WO 04/098457A1 provides a method comprising using organic particles as a porogen. The method comprises the steps of mixing the pore formation agent and ceramic powder, shaping the mixture by pressing, and then sintering. The closed-cell type pores are formed as spaces left by the gasification of the organic compounds during sintering. Although pore formation agents are effective in the formation of a porous structure, the mechanical strength of the resulting product is inadequate.
3. Polyurethanes (PU) Sponge with High Porosity as a Mold
US 20060198939 provides a production method for porous open-cell ceramic composites coated with a biodegradable polymer for use as a bone substitute. This reference uses a highly porous polyurethane (PU) sponge as a template. The PU sponge is immersed into calcium phosphate slurry several times to ensure the pore structure of the PU is covered by calcium phosphate. After carefully drying, the PU sponge is removed by gasifying during sintering procedure at a high temperature. A calcium phosphate substrate with open-cell pores is obtained. However, the mechanical strength of the acquired substrate is inadequate. For this reason, the substrate is need further procedure of soaking in a polycaprolactone (PCL) solution and then dried in room temperature to enhance its mechanical property by PCL coating.
4. Foaming
US 20070218098 relates to a foaming method of produced porous calcium phosphate. The pore structure is foamed by the CO2 which is produced by heating ammonium carbonate. Besides, US 20080069852 provides another foaming method by using a supercritical fluid. However, the foaming process is usually unstable and the resulted pore size is difficult to control.
5. Computer-Assisted Design and Manufacture Method
U.S. Pat. No. 6,905,516 mentions a special mold method that is designed and created by use of a computer program. The calcium phosphate slurry is infused into the mold. The structure is solidified to form hydroxyapatite and then porous structure is formed after de-molding. Interconnected pores can be generated by this method. However, the design equipment is usually expensive and the process is time-consuming.
In spite of various improvements to the processes, preparation of porous 3D open-cell bone substitutes remains significantly complex. There is a compelling need to develop a more rapid, simple, inexpensive, and reliable method of preparing bone substitutes with the required interconnective porous structures and mechanical properties.